Compounds used to treat alcoholism

ABSTRACT

N,N′-bis(3-aminopropyl)cyclohexane-1,4-diamine, of formula (I), is a new compound that is prepared by hydrogenation with Raney nickel catalyst of N,N′-bis(2-cyanoethyl)-cyclohexane-1,4-diamine, the latter being prepared by reaction between 1,4-cyclohexanediamine and acrylonitrile. The oral administration to genetically alcoholic rats (from the strain UChB of the University of Chile) of the tetrametanesulfonate monohydrate of (I) causes a significant reduction in the alcohol consumption. The activity lasts for some time after the treatment period. Besides, there is a virtually null disulfiram-like adverse effect, what constitutes an advantage over the unpleasant use of some anti-alcoholism agents, such as calcium cyanamide or disulfiram itself. Therefore, the compounds of the invention are useful for the preparation of medicaments for the therapeutic and/or prophylactic treatment of alcoholism in mammals, including human beings.

[0001] This invention relates to new compounds, their preparationprocess and their use for preparing compositions for the treatment ofalcoholism in mammals, including human beings.

BACKGROUND ART

[0002] The expression “treatment of alcoholism” comprises the reductionof the desire for and habit of consuming alcoholic drinks, the treatmentof alcohol dependence and the treatment of abstinence syndrome.Alcoholism may be viewed as a disease, a drug addiction, a learnedresponse to crisis, a symptom of an underlying psychological or physicaldisorder, or a combination of these factors. Most approaches to thetreatment of alcoholism require the alcoholic person to recognizehis/her illness and to abstain from alcohol. Treatment programs thenvary according to the accepted definition and theory of cause ofalcoholism. Treatment types include combinations of: psychologicalrehabilitative treatments; organized self-help groups; aversion therapybased on behavior modification; injections of vitamins or hormones, andthe use of abstinence-maintaining drugs. The present invention relatesto the latter type of treatments.

[0003] One of the drug treatments of alcoholism, initiated in 1948 byEric Jacobsen of Denmark, uses disulfiram (tetraethylthiuram disulfide),of formula Et₂N—C(═S)—S—S—C(═S)—NEt₂. The usual technique is toadminister half a gram in tablet form daily for a few days; then, undercarefully controlled conditions and with medical supervision, thepatient is given a small drink of an alcoholic beverage. The presence ofdisulfiram in the drinker's body causes a reaction of hot flushing,nausea, vomiting, a sudden sharp drop of blood pressure, pounding of theheart, and even a feeling of impending death. These symptoms, usuallyknown as ‘acetaldehyde syndrome’ or ‘disulfiram-like adverse effect’,result from an accumulation of the highly toxic first product of alcoholmetabolism, acetaldehyde. Normally, as alcohol is converted toacetaldehyde, the latter is rapidly converted, in turn, to otherharmless metabolites; but in the presence of disulfiram—itselfnon-toxic, although not completely innocuous—the metabolism ofacetaldehyde is blocked, with the resulting toxic symptoms. The patientis thus dramatically shown the danger of attempting to drink while underdisulfiram medication. A smaller daily dose of disulfiram is thenprescribed, and the dread of the consequences of drinking acts as achemical fence to prevent the patient from drinking as long as hecontinues taking the drug.

[0004] Besides being quite unpleasant for patients, treatment ofalcoholism with disulfiram involves a high risk, because subjectstreated with disulfiram suffer from very serious symptoms deriving fromthe ingestion of even small doses of alcohol. Thus, following disulfiramtreatment cases of respiratory depression, cardiovascular collapse,cardiac arrhythmia, myocardium infarct, and sudden or unexpected deathhave occurred.

[0005] Citrated calcium cyanamide (two parts of citric acid by weight toone part of CaNCN) is another drug used as anti-alcoholism agent, whichhas a disulfiram-like mechanism of action. It is preferred by sometherapists because the reaction with alcohol is milder than in the caseof disulfiram, though its protective potency is briefer. Othersubstances that can produce disagreeable reactions with alcohol includeanimal charcoal, the mushroom Coprinus atramentarius, numerousantidiabetic drugs, and the pine Lycopodium selago; however they haveattracted very little clinical interest. Thus, in the last years, therehave been an active research of other drugs to fight alcoholism withouthaving the “disulfiram-like adverse effect”, i.e., without producingdisagreeable reactions with alcohol.

[0006] Many anti-alcoholism agents have been proposed, among which thereare the following: opioid antagonists, such as naltrexone, naloxone andnalmefene (cf. U.S. Pat. No. 4,882,335 and U.S. Pat. No. 5,086,058);acyl L-carnitine gamma-hydroxybutyrates (cf. EP 616,805-A1),gamma-hydroxybutyric acid salts (cf. U.S. Pat. No. 4,983,632) andgamma-hydroxybutyric acid amides (cf. WO 9806690-A1);2-pyrimidinyl-1-piperazine derivatives such as ipsapirone (cf. U.S. Pat.No. 4,895,848); pyrrolidine derivatives (cf. U.S. Pat. No. 5,935,980);cholinesterase inhibitor, such as galanthamine (cf. U.S. Pat. No.5,932,238); serotonin reuptake inhibitors, such as fluoxetine, and thecombination of the later with opioid antagonists (cf. WO 9609047-A1).

[0007] Acamprosate calcium (cf. U.S. Pat. No. 4,355,043), of formula(CH₃—CO—NH—CH₂—CH₂—CH₂—SO₃)₂Ca, is one anti-alcoholism agent which isbeing used in practice. However, it has been mentioned that the use ofthis compound is far from being satisfactory, and that the evidence isnot strong enough to support the introduction of this substance intoroutine clinical practice at present (cf. Moncrieff et al., “New drugtreatments for alcohol problems: a critical appraisal”, Addiction 1997,vol. 92, pp. 939-47; discussion in pp. 949-64). Thus, apparently none ofthe proposed treatments of alcoholism has proved to be completelysatisfactory in practice, and the pharmacological fight againstalcoholism is far from being solved.

DESCRIPTION OF THE INVENTION

[0008] According to an aspect of the present invention, it is provided anew compound of formula (I) or a physiologically-hydrolysable andacceptable amide of it, a stereoisomer or a mixture of stereoisomers ofsaid compound (I) or of said amide, or a pharmaceutically acceptablesalt or a pharmaceutically acceptable solvate thereof.

[0009] By the expression physiologically-hydrolysable and acceptableamide of (I) it is meant any amide of compound (I) in which one orseveral of its amine groups have formed amide groups withphysiologically-acceptable acids, and in which said amide groups arehydrolysable under physiological conditions to yield acids which arethemselves physiologically tolerable at dosages to be administered. Theexpression is thus to be understood as defining amides which arebioprecursor forms of compound of formula (I), i.e., pharmaceuticallyacceptable biologically degradable amides of the compound of formula (I)which, upon administration to a human being, are converted in the bodyto produce the compound of formula (I). Examples of such bioprecursorsinclude amides of (I) with acetic acid, propionic acid, benzoic acid,methanesulfonic acid, benzenesulfonic acid and 4-methylbenzenesulfonicacid.

[0010] Compounds of the present invention can be in two differentstereochemical forms, namely cis and trans in respect of the1,4-substitution of the cyclohexane ring. The invention refers to bothforms substantially pure, as well as to their mixtures.

[0011] In preferred embodiments of the present invention the compound isN,N′-bis(3-aminopropyl)cyclohexane-1,4-diamine, of formula (I), or apharmaceutically acceptable salt or a pharmaceutically acceptablesolvate thereof.

[0012] By pharmaceutically acceptable salt it is meant any addition saltwith one or more physiologically tolerable acid at doses to beadministered. Examples of these acids are inorganic acids such as HCl,HBr, HI, HNO₃, H₂SO₄, etc.; and organic acids such as acetic acid,benzoic acid, methanesulfonic acid, benzenesulfonic acid,4-methylbenzenesulfonic acid, etc. In a preferred embodiment thepharmaceutically acceptable salt is the tetrametanesulfonate.

[0013] By pharmaceutically acceptable solvate it is meant any solvatewith a solvent which is physiologically tolerable at doses to beadministered, e.g. water. In a preferred embodiment, the compound of thepresent invention is N,N′-bis(3-aminopropyl)cyclohexane-1,4-diaminetetrametanesulfonate monohydrate, a compound here prepared for the firsttime, whose therapeutic activity is illustrated in the accompanyingexamples.

[0014] According to another aspect of the present invention, there isprovided a preparation process ofN,N′-bis(3-aminopropyl)cyclohexane-1,4-diamine, of formula (I),comprising the reduction ofN,N′-bis(2-cyanoethyl)-cyclohexane-1,4-diamine of formula (II). In apreferred embodiment, this reduction is carried out by hydrogenationwith Raney nickel catalyst.

[0015] In a preferred embodiment of this preparation process, dinitrile(II) is prepared by reaction between 1,4-cyclohexanediamine andacrylonitrile (CH₂═CH—CN), the later two reactants being commerciallyavailable.

[0016] The above-mentioned reactions are carried out in conditionscommon in the art, illustrated in the accompanying examples. When1,4-cyclohexanediamine is in a substantially pure stereochemcial form(cis or trans), the corresponding stereoisomers (cis or trans) of (II)and (I) are obtained. Preparation of salts of (I) (e.g.tetrametanesulfonate) is carried out by reaction with the correspondingacid (e.g. metanesulfonic acid) in a suitable solvent or mixture ofsolvents for precipitation of the salt.

[0017] The invention also relates to a method of therapeutic and/orprophylactic treatment of a patient suffering from alcoholism,comprising the administration of at least one of the compounds of theinvention, together with pharmaceutically acceptable excipients orcarriers. Thus, another aspect of the present invention is the use ofthe compounds of the invention for the preparation of a medicament forthe therapeutic and/or prophylactic treatment of alcoholism in mammals,including human beings.

[0018] As illustrated in accompanying Examples, carried out with ananimal model which is extrapolated to human beings, the compounds of thepresent invention cause a significant reduction in the alcoholconsumption in mammals. The extent of this reduction depends on the doseand the duration of the treatment.

[0019] Pharmaceutical compositions of the anti-alcoholism compounds ofthe invention can be prepared in formulations suitable for oral orparental administration, according to the particular requirements of theapplication. Oral formulations are specially preferred. As well known bypersons skilled in the art, the choice of excipients in the formulationsdepends not only on the chemical and physical characteristics of theactive principle and the required posology, but also on the type ofcomposition desired. Besides, the dosage of the active principleobviously varies in accordance with the body weight of the patient andhis clinical condition. Typical doses are those between 1 and 100 mg ofcompound per kg, those between 20 mg/kg and 40 mg/kg being preferred.

[0020] An advantage of the present invention is that the anti-alcoholismactivity of the compounds lasts for some time after the treatmentperiod, what can allow a decrease in the dose, or even a total cure ofthe patient.

[0021] Another advantage of the present invention, in comparison withthe unpleasant use of disulfiram, calcium cyanamide and otheranti-alcoholism agents, is that the disulfiram-like adverse effect isvirtually null. This probably indicates that the activity of thecompounds of the present invention does not respond to a disulfiram-likemechanism of action.

[0022] The invention is illustrated by the following non-limitingexamples.

EXAMPLES Example 1 Preparation ofN,N′-bis(2-cyanoethyl)-cyclohexane-1,4-diamine (II)

[0023] In a 5-liter reactor, 531.5 g of 1,4-cyclohexanediamine wereplaced and warmed at 80° C. until total fusion of the product. Then 675mL of acrylonitrile were added and the mixture was warmed at 80° C. for1 h, and at 100° C. for 2 h. Then 960 mL of ethanol were added and itwas cooled down to room temperature, occurring the precipitation of asolid. After filtering, washing with ethanol and drying, 952.2 g (92.8%)of the title compound were obtained as a brown solid. Elemental analysis(%): theory, C, 65.49; H, 9.09; N, 25.45; found, C, 65.80; H, 9.20; N,26.16.

Example 2 Preparation of N,N′-bis(3-aminopropyl)cyclohexane-1,4-diamine(I)

[0024] A solution of 952.2 g ofN,N′-bis(2-cyanoethyl)-cyclohexane-1,4-diamine (II) in 21.2 L ofmethanol was prepared and it was then saturated with ammonia. In a50-liter hydrogenation reactor the solution was hydrogenated at 50° C.and a hydrogen pressure of 4 bar, for 40 h, with 200 g of Raney nickelcatalyst. After filtering off the catalyst and distilling the solvent,924.4 g (93.7%) of the title compound were obtained as a green oil.¹H-NMR spectrum (δ, ppm, CDCl₃): 1.05 (m, 4H), 1.48-1.66 (m, 10H), 1.92(m, 4H), 2.35 (m, 2H), 2.65-2.79 (m, 8H). “C-NMR spectrum (δ, ppm,CDCl₃) 31.8 (cyclohexane CH₂), 33.9 (CH₂), 40.1 (CH₂—NH₂), 44.7(CH₂—NH), 56.6 (cyclohexane CH). IR spectrum (cm⁻¹, KBr): 3272 (NH₂,NH), 2940 (aliphatic CH).

Example 3 Preparation of N,N′-bis(3-aminopropyl)cyclohexane-1,4-diaminetetramethanesulfonate monohydrate

[0025] A solution of 350 mL of methanesulfonic acid in 1345 mL of ethylacetate was added to a solution of 285.8 g ofN,N′-bis(3-aminopropyl)cyclohexane-1,4-diamine (I) in 6880 mL ofmethanol. After stirring for 2 h, filtering, washing with ethanol anddrying, 625 g of a crude solid were obtained. The solid was treated andstirred with water (5 mL per gram of solid) and activated charcoal for 2h. After filtering off the charcoal, evaporating the water under vacuum,and drying at 40° C. until constant weight, 515 g (67.2%) of the titlecompound were obtained, with a melting point of 261-5° C. ¹H-NMRspectrum (δ, ppm, DMSO-d₆): 1.4 (m, 4H), 1.91 (m, 4H), 2.14 (m, 4H), 2.3(s, 12H), 2.90 and 3.20 (m 10H), 8 (10H). ¹³C-NMR spectrum (δ, ppm,DMSO-d₆): 22.4 (cyclohexane CH₂), 24.6 (CH₂), 34.6 (CH₂—NH₂), 38.5 (acidCH₃), 38.6 (acid CH₃), 39.6 (CH₂—NH), 52.9 (cyclohexane CH). IR spectrum(cm⁻¹, KBr): 3440 (H₂O), 2944, 2860 (aliphatic CH), 1195 (SO₃).Elemental analysis (%) theory, C, 30.48; H, 7.30; N, 8.88; found, C30.79, H 7.04, N 8.88.

Example 4 Anti-Alcoholism Activity of Compound (I) inGenetically-Alcoholic Rats

[0026] As an animal model of alcoholic mammals, including human beings,adult Wistar rats of both sexes, belonging to the UChB strain were used.This strain of rats is the result of a long selection at the Universityof Chile, and rats belonging to it are known to be volunteer consumersof 10% (v/v) aqueous alcohol (cf. J. Mardones and N. Segovia-Riquelme,“Thirty two years of selection of rats by ethanol preference”: UChA andUChB strains”, Neurobehav. Toxicol. and Teratol. 1983, vol. 5, pp.171-178). Thus, the rats used in these experiments can be consideredgenetically alcoholic.

[0027] Rats were kept in individual cages at 22° C., with alternative 12h periods of light and darkness. Besides unlimited access to food, theyhad ad libitum access to water and 10% (v/v) aqueous alcohol. Allexperiments were double-blind, and results were analyzed using commonstatistical methods. As changes in alcohol consumption might beinfluenced by the eagerness of food and/or water intake, both theconsumption of food and of water were measured and analyzed. However,experimental changes in the consumption of both food and water were notsignificant. In each experiment the following three periods of time wereconsidered:

[0028] a) A reference period, consisting of the three days previous totreatment. The measured consumption values were used as reference forcomparison purposes.

[0029] b) A treatment period, consisting of the three or six days duringwhich aqueous solutions of the tested compound were intra-gastricallyadministered, always at the same time of the day.N,N′-bis(3-aminopropyl)cyclohexane-1,4-diamine tetramethanesulfonatemonohydrate was administered at two doses, 20 mg/kg of body weight and40 mg/kg, using aqueous solutions of the tested compound ofconcentrations 10 g/L and 20 g/L, respectively. Dose of 20 mg/kg wastested both for 3 consecutive days and 6 consecutive days. Dose of 40mg/kg was tested only for 3 consecutive days.

[0030] c) A post-treatment period, consisting of the three daysimmediate after the treatment period, during which measurement weretaken in order to establish the duration of the effect and thereversibility of the changes.

[0031] It was observed that treatment with 20 mg/kg for 6 dayssignificantly (p<0.01) lowered alcohol consumption in a 25%, along thefirst 6 hours after administration. Treatment with 40 mg/kg for 3 dayssignificantly lowered alcohol consumption in a 27%, and this decreasewas kept along the post-treatment period. Decreases of alcoholconsumption in the period of 6-24 h were smaller, what is associatedwith a reduction of concentration of active substance in blood.

[0032] Overall results indicate thatN,N′-bis(3-aminopropyl)cyclohexane-1,4-diamine tetramethanesulfonatemonohydrate has a substantial activity as anti-alcoholism agent. Itseffect depend on treatment duration and dose.

Example 5 Anti-Alcoholism Activity of Compound (I) During a ProlongedTreatment Period

[0033] The effect of the administration ofN,N′-bis(3-aminopropyl)-cyclohexane-1,4-diamine tetramethanesulfonatemonohydrate to Wistar rats of both sexes belonging to the UChB strain,at a dose of 40 mg/kg during a treatment period of 30 days, was assessedin an experiment analogous to the one of Example 4. Individualconsumptions of alcohol and water, measured daily, were grouped incycles of 3 consecutive days, thus reducing data to ten average values.Results showed a gradual decrease in alcohol consumption reaching a 71%decrease at the end of the treatment period. Water consumption showed agradual increase, reaching more than 200%.

Example 6 Anti-Alcoholism Activity of Compound (I) During aPost-Treatment Period

[0034] The effect of the administration ofN,N′-bis(3-aminopropyl)-cyclohexane-1,4-diamine tetramethanesulfonatemonohydrate to Wistar rats of both sexes belonging to the UChB strain,during a post-treatment period of 27 days (9 cycles of 3 days) after theprolonged treatment of Example 5, was assessed in an analogousexperiment. Results showed a gradual recovery in alcohol consumption,reaching a decrease of 24% at the end of the period. At the end of thepost-treatment period, water consumption, which had reached more than200% as a result of the prolonged treatment, decreased to 171% of theinitial value. Therefore, the effect ofN,N′-bis(3-aminopropyl)-cyclohexane-1,4-diamine tetramethanesulfonatemonohydrate lasts substantially for a long time after a prolongedtreatment, without recovering the initial levels of alcohol/waterconsumption.

Example 7 Assessment of Disulfiram-Like Adverse Effect

[0035] The possible disulfiram-like adverse effect ofN,N′-bis(3-aminopropyl)cyclohexane-1,4-diamine tetramethanesulfonatemonohydrate was studied by gas-chromatographic measurements of the bloodconcentration of acetaldehyde in standard Wistar male rats, after theintraperitoneal administration of 2.76 g/kg of ethanol in the form of10% (v/v) aqueous solution. Blood samples were taken from the tail (0.5,1.0 and 2.0 h after ethanol administration) and from the suprahepaticvein (2.0 h after ethanol administration). It was observed that previousoral administration of the tested compound at a dose of 40 mg/kg (2, 6,8 and 24 h before ethanol administration) did not raised levels ofacetaldehyde in blood. It is then concluded that the tested compounddoes not block the metabolism of acetaldehyde significantly (contrary towhat happens with disulfiram, as it was observed in a control test).

1. A compound of formula (I) or a physiologically-hydrolysable andacceptable amide of it, a stereoisomer or a mixture a stereoisomers ofsaid compound or of said amide, or a pharmaceutically acceptable salt ora pharmaceutically acceptable solvate thereof.


2. A compound according to claim 1, characterized in that it isN,N′-bis(3-aminopropyl)cyclohexane-1,4-diamine, of formula (I), astereoisomer or a mixture a stereoisomers of it, or a pharmaceuticallyacceptable salt or a pharmaceutically acceptable solvate thereof.
 3. Acompound according to any of the claims 1 or 2, wherein thepharmaceutically acceptable salt is the tetramethanesulfonate. 4.N,N′-bis(3-aminopropyl)cyclohexane-1,4-diamine tetrametanesulfonatemonohydrate.
 5. Process for the preparation ofN,N′-bis(3-aminopropyl)cyclohexane-1,4-diamine, of formula (I),comprising the reduction ofN,N′-bis(2-cyanoethyl)-cyclohexane-1,4-diamine, of formula (II).


6. Process according to claim 5, wherein the reduction is carried out byhydrogenation with Raney nickel catalyst.
 7. Process according to any ofthe claims 5 or 6, further characterized in that the nitrile of formula(II) is prepared by reaction between 1,4-cyclohexanediamine andacrylonitrile.
 8. A compound as defined in any of the claims 1 to 4 asactive substance of a medicament.
 9. A compound as defined in any of theclaims 1 to 4 for the therapeutic and/or prophylactic treatment ofalcoholism in mammals, including human beings.
 10. Use of a compound asdefined in any of the claims 1 to 4, for the preparation of a medicamentfor the therapeutic and/or prophylactic treatment of alcoholism inmammals, including human beings.